Synthesis of structure-defined /3-1,4-GlcNAc-modified wall teichoic acids as potential vaccine against methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) is a high priority pathogen due to its life-threating infections to human health. Development of prophylactic or therapeutic anti-MRSA vaccine is a potential approach to treat S. aureus infections and overcome the resistance crisis. /3-1,4-GlcNAc glycosylated wall teichoic acids (WTAs) derived from S. aureus are a new type of antigen that is closely associated with 8-lactam resistance. In this study, structure-defined /3-1,4-GlcNAc-modified WTAs varied in chain length and numbers of GlcNAc modification were synthesized by an ionic liquid-supported oligosaccharide synthesis (ILSOS) strategy in high efficiency and chromatography-free approach. Then the obtained WTAs were conjugated with tetanus toxin (TT) as vaccine candidates and were further evaluated in a mouse model to determine the structure-immunogenicity relationship. In vivo immunological studies revealed that the WTAs-TT conjugates provoked robust T cell-dependent responses and elicited high levels of specific anti-WTAs IgG antibodies production associated with the WTAs structure including chain length as well as the /3-1,4-GlcNAc modification pattern. Heptamer WTAs conjugate T6, carrying three copy of /3-1,4-GlcNAc modified RboP, was identified to elicit the highest titers of specific antibody production. The T6 antisera exhibited the highest recognition and binding affinity and the most potent OP-killing activities to MSSA and MRSA cells. This study demonstrated that /3-1,4-GlcNAc glycosylated WTAs are promising antigens for further development against MRSA.

Automated summary

In this study, glycosylated wall teichoic acids (WTAs) derived from S. aureus were modified and conjugated with tetanus toxin (TT) as potential MRSA vaccine candidates. The structure-immunogenicity relationship was evaluated in a mouse model, and the heptamer WTAs conjugate T6 showed the highest specific antibody production.